Aging of an organism is associated with a gradual impairment of cellular functions and viability. This is due to an increased impact of various metabolic, dietary or environment derived insults upon cells and associated with diminished capacity of cells to cope with these changes during aging. This imbalance between harmful exposures and protection leads to heterogeneous progressive chronic diseases such as atherosclerosis and neurodegeneration as well as predisposes target organs to further cellular injury in acute conditions like myocardial or cerebral ischemic stroke.
Due to the changes in life styles and increasing number of aged people globally, the socio-economic burden of diseases and states associated with cellular damage is increasing exponentially. While the symptomatic therapy of many age-associated diseases and conditions has progressed considerably, there remains a huge need to prevent, delay the onset, or slow down the expected progression of cellular degeneration underlying these diseases. Such peripheral and central degenerative diseases and conditions associated with aging include Alzheimer's disease and other forms of dementia, amyotrophic lateral sclerosis, atherosclerosis, cancer, Huntington's disease, ischemic or hemorrhagic stroke, liver cirrhosis and non-alcoholic liver diseases, metabolic disorders, multiple sclerosis, noise induced hearing loss, Parkinson's disease, retinal degeneration, and renal diseases.
It has become apparent that while such diseases or states may have their unique etiological factors, they share many common molecular mechanisms leading to impaired function and reduced cellular viability in various target organs and their compartments. Lipids, proteins and DNA are sensitive to oxidative damage. One common pathological feature of age-associated diseases is increased and aberrant oxidation of lipids (reviewed for example in Negre-Salvayre et al. Free Radic Res 2010 44(10):1125-1171), which is known to be an important factor leading to cell death.
The process of lipid peroxidation is mediated through both enzymatic and non-enzymatic pathways. Enzymatic pathways involve lipo-oxygenases and cyclo-oxygenases acting at the polyunsaturated fatty acids (PUFAs) present as free or engaged in lipid complexes such as cell membrane phospholipids or lipoproteins. Non-enzymatic reactions on PUFAs (such as linoleic acid, arachidonic acid) involve ferryl radical, peroxynitrite, hydroperoxyl and hydroxyl radicals among others as possible mediators. Several factors, such as impaired mitochondrial function or inflammation, occurring in central nervous system and peripheral disorders can contribute to the generation of the above mentioned reactive oxygen and nitrogen mediators attacking vital phospholipid components in biological membranes. Lipid hydroperoxides (LOON) themselves are reactive oxygen species capable of oxidizing other macromolecules. Majority of the lipid hydroperoxides is, however, converted non-enzymatically to secondary products including electrophiles causing further dysfunction and damage in cells and leading to the acceleration of secondary lipid peroxidation and ultimately to cell death. Enhanced lipid peroxidation also contributes to the generation of inflammatory response and propagation of inflammatory processes in diseased tissues.
Diseases or states, either acute or chronic, involving aberrant cellular lipid peroxidation in the central nervous system or in the periphery of the body are known to include Alzheimer's disease and other forms of dementia including tauopathies, such as frontotemporal dementia and parkinsonism linked to chromosome 17, progressive supranuclear palsy and corticobasal degeneration, amyotrophic lateral sclerosis, atherosclerosis, cancer, Huntington's disease, ischemic or hemorrhagic stroke, ischemic bowel disease and limb ischemia, liver cirrhosis and non-alcoholic liver diseases, metabolic disorders, multiple sclerosis, myocardial ischemia, noise induced hearing loss, Parkinson's disease, retinal degeneration, renal diseases as well as traumatic brain or spinal cord injury, radiation associated normal tissue injury, liver transplantation induced stenosis, neonatal hypoxic-ischemic injury, adverse cerebral outcomes after cardiac bypass surgery, and HIV-associated neurocognitive disorders.
The cells employ various enzymatic and chemical reactions to defend against the formation and accumulation of lipid hydroperoxides. However, the function of most of the cellular antioxidant systems is dependent on reducing equivalents such as glutathione, which is depleted upon aging and in early stages of pathogenic processes, rendering these defense mechanisms vulnerable.
Therefore, treatment strategies based on elimination of lipid hydroperoxides and limiting their detrimental effects on cellular macromolecules is expected to provide cytoprotection and be of great advantage in the treatment or prophylaxis of age-associated degenerative diseases and other states related to aberrant lipid peroxidation. An object of the present disclosure is to provide compounds useful as cytoprotectants and which may be used for the treatment or prophylaxis of peripheral and central degenerative disorders, in particular in the treatment of mammals, including humans.
Known from CAPlus-database and available from commercial sources are 4,4-dimethyl-2,4,5,6-tetrahydropyrazolo[4,3-c]phenothiazine and 4,4-dimethyl-2-phenyl-2,4,5,6-tetrahydropyrazolo[4,3-c]phenothiazine which fall under the definition of the present invention. However, no field of use or identification data is given for these molecules.